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SUMMARY

Cancer is driven by alterations in biological pathways. In particular, the laboratory of Viji Shridhar, Ph.D., is interested in two major biological pathways altered in cancer: growth factor signaling pathways and programmed cell death pathways.

One of the major focuses of her research program is to understand how HSulf-1 regulates growth factor signaling in ovarian and breast cancer and contributes to cancer development and progression. Another major focus of her research program is to understand how HtrA1 regulates programmed cell death pathways and contributes to chemotherapy resistance.

Current studies are aimed at determining both the mechanism of loss and the functional consequences of loss of these potential novel tumor suppressor genes in promoting tumorigenesis, metastasis and chemoresistance in ovarian and breast cancers.

The other focus of Dr. Shridhar's research program is to translate basic research to bedside to help patients with ovarian or breast cancer by repositioning drugs such as metformin and drugs that target the tumor microenvironment to inhibit metastasis and minimize residual disease.

Focus areas

Role of HSulf-1 in cancer. Dr. Shridhar's lab has previously shown that loss of HSulf-1 in ovarian and breast cancer promotes tumorigenesis, angiogenesis and resistance to commonly used chemotherapeutic agents. The lab has identified how expression of HSulf-1 is regulated at the transcriptional level to promote cancer growth both in vitro and in vivo. Ongoing studies have identified previously unknown pathways regulated by loss of HSulf1, namely autophagy and lipid droplet (LD) biogenesis. LDs are intracellular organelles that store neutral lipids for metabolic energy and to synthesize membranes in cells.

Increased expression of several enzymes involved in lipid synthesis and metabolism, such as fatty acid synthase (FASN), cytosolic phospholipase A2 (cPLA2) and D, and sphingosine kinase 1 (SPHK1), in ovarian cancer is linked to increased proliferation, growth, migration, invasion and resistance to chemotherapy, making them all ideal therapeutic targets. Increased activity of these enzymes that promote fatty acid synthesis and LD accumulation occurs very early in cancer development and is more pronounced in aggressive tumors of different origins (breast, colon, brain and ovarian), implicating changes in the lipogenic pathway as one of the most common molecular changes associated with the development and progression of cancer.

Current studies are focused on therapeutically targeting lipid droplets as a disease marker in ovarian cancer and determining the role of HSulf-1 in regulating autophagy and LD formation.

Functional consequences of loss of HtrA1 in ovarian cancer. This project is designed to understand the role of HtrA1, particularly in programmed cell death and in modulating chemoresponse. HtrA1 was identified from suppression subtraction cDNA library as a downregulated tumor suppressor gene in 50 percent of ovarian cancers. Dr. Shridhar's group is proposing a novel concept: that HtrA1 is a component of a "serine proteosome" involving other members of the HtrA family, since the increased cell death depends on the protease activity of HtrA1.

Testing the efficacy of drugs that target tumor metabolism and the tumor microenvironment. Dr. Shridhar's lab has tested metformin, a Food and Drug Administration-approved drug used in the treatment of patients with diabetes, to see if it will inhibit growth of ovarian cancer. The laboratory is also testing the efficacy of PG545, a heparan sulfate mimetic that targets the tumor microenvironment in inhibiting ovarian cancer metastasis and minimizing residual disease.

Significance to patient care

Dr. Shridhar's laboratory has identified a previously unknown pathway regulated by loss of HSulf-1, namely the generation of LDs. Since LDs are associated with ovarian cancer metastasis and chemoresistance, the lab's discovery that a gene that is commonly lost in ovarian cancer regulates LDs opens new avenues to target LDs (as a disease marker) with pharmacological and molecular-based approaches and reverse the cancer phenotype associated with loss of this gene.

Testing of novel drugs (PG545 is currently in a phase I clinical trial) and repositioning drugs (metformin) in preclinical models will lead to testing of these drugs in clinical trials to improve patient care.

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